Project Summary/Abstract Alzheimer?s disease (AD) and Frontotemporal dementia linked to chromosome 17 (FTDP-17) are characterized by a progressive decline in memory and other cognitive functions that ultimately result in dementia. Amyloid ? (A?) plaques and neurofibrillary tangles made up of hyperphosphorylated Tau are the two hallmark features of AD. Although no mutation in the Tau gene has been identified to cause AD, FTDP-17 can be caused by the P301L mutation. Fyn, a Src family non-receptor tyrosine kinase (SFK), has recently been implicated in AD. A? activates Fyn to cause behavioral deficits, Tau hyperphosphorylation, and downregulation of N-methyl-D-aspartate receptors (NMDAR) at the synapse. Previously, our laboratory discovered that wild type Tau (TauWT) upregulates Fyn activity and mutant Tau (TauP301L) has increased affinity for Fyn. Missing from our current knowledge is the role of the Fyn-Tau interaction in both normal physiological functions and in FTDP-17 where A? is absent. This proposal is based on our hypothesis that during disease pathogenesis, an interaction between Tau and Fyn serves as a key event leading to neurodegeneration. To investigate the role of the Fyn-Tau interaction in both normal functions and neurodegeneration, we will first create a Fyn-/-/Tau-/- mouse and then induce Tau pathology by injecting Adeno-associated virus (AAV) expressing TauP301L (AAV TauP301L) into the ventricles of the double knockout mouse on postnatal day 0 (p0). We propose the following specific aims: 1) Characterize behavioral and biochemical properties of Fyn-/-/Tau-/- mice. We will perform various behavioral and biochemical assays starting with areas where single knockout animals display deficits in order to identify pathways that are affected by both Fyn and Tau. Fyn-/-, Tau-/-, and WT mice will be used as controls. The results obtained from this aim will also serve as a control for experiments in specific aim 2. 2) Determine how Fyn depletion affects TauP301L induced neurodegeneration in an FTDP-17 mouse model. We will create Fyn-/-/Tau-/-(AAV TauP301L) animals and use behavioral, biochemical and immunohistochemical assays to compare the properties of this mouse against those of Tau-/-(AAV TauP301L) animals. Fyn-/-/Tau-/-(AAV TauWT), Tau-/-(AAV TauWT), Fyn-/-/Tau-/-, and Tau-/- will be used as controls. Our proposal will investigate the interaction between Fyn and Tau during both normal neuronal function and during the neurodegenerative process in an FTDP-17 mouse model. Our research may establish Fyn as a critical protein involved in the pathogenesis of tauopathies. Understanding the interaction between Fyn and Tau may lead to the development of therapeutics to slow or halt neurodegeneration.